Blood filtering of inflammatory biomarkers to treat post-resuscitation syndrome

ABSTRACT

Provided is a therapeutic device that includes tubing; at least one pump; and a column or filter capable of removing leukocytes, cytokines, and/or other blood components from the blood of a patient to effectively treat or prevent post-resuscitation syndrome. Methods for treating and/or preventing post-resuscitation syndrome that include the use of such a device, or a filter or column capable of selectively removing inflammatory biomarkers, are also provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. application Ser. No.14/669,930, filed Mar. 26, 2015, which claims the benefit under 35U.S.C. § 119(e) of U.S. Provisional Application No. 61/972,827, filedMar. 31, 2014. The disclosures of each of the above-identifiedapplications, including the specification, drawings, and claims, areexpressly incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to methods of treating or preventingpost-resuscitation syndrome (PRS) comprising filtering or removinginflammatory biomarkers and/or other blood components from a subject.The invention also relates to a therapeutic device for treatingpost-resuscitation syndrome.

Background of the Invention

Post-resuscitation syndrome (PRS) describes a complex cascade ofphysiologic events following a cardiac arrest and/or other loss ofcirculation that remains difficult to treat. PRS shares much in commonwith the classic condition of sepsis. PRS is characterized byhyperthermia, hypotension, and multiple organ failure (Laurent, J. Am.Coll. Cardiol. 46(3):432-37, 2005, which is incorporated by referenceherein in its entirety). PRS is also known as post-cardiac arrestsyndrome because the term post-resuscitation implies that the act ofresuscitation is complete (Nolan et al., Resuscitation 79:350-379, 2008,which is incorporated by reference herein in its entirety). However, themore complex phase of resuscitation begins after patients regainspontaneous circulation. Id.

PRS includes the following pathophysiological processes: (1)post-cardiac arrest brain injury, (2) post-cardiac arrest myocardialdysfunction, and (3) systemic ischemia/reperfusion response. (Nolan etal., Resuscitation 79:350-379, 2008). Of course, the syndrome isgenerally further complicated by the original pathological factors thatlead to the initiating cardiac arrest (Nolan et al., Resuscitation79:350-379, 2008).

Post-cardiac arrest brain injury may result in impaired cerebrovascularautoregulation, cerebral edema, and/or post-ischemic neurodegeneration.Clinical manifestations include coma, seizures, myoclonus, cognitivedysfunction, persistent vegetative state, secondary Parkinsonism,cortical stroke, spinal stroke, and brain death (Nolan et al.,Resuscitation 79:350-379, 2008).

Post-cardiac arrest myocardial dysfunction may result in globalhypokinesis (myocardial stunning), reduced cardiac output, and acutecoronary syndrome. Clinical manifestations include earlyrevascularization of acute myocardial infarction, hypotension,dysrhythmias, and cardiovascular collapse (Nolan et al., Resuscitation79:350-379, 2008).

Systemic ischemia/reperfusion response may result in systemicinflammatory response syndrome, impaired vasoregulation, increasedcoagulation and/or coagulation abnormalities, adrenal suppression and/ordysfunction, impaired tissue oxygen delivery and utilization, andimpaired resistance to infection. Clinical manifestations includeongoing tissue hypoxia/ischemia, hypotension, cardiovascular collapse,pyrexia (fever), hyperglycemia, multi-organ failure, and infection(Nolan et al., Resuscitation 79:350-379, 2008).

PRS has also been associated with complement activation, improperregulation of cytokine production by leukocytes, expression of adhesionmolecules, cytokine release, and endotoxin presence in plasma (Laurentet al., J. Am. Coll. Cardiol. 46(3):432-37, 2005; and Adrie et al.,Curr. Opin. Crit. Care 10:208-212, 2004, which is incorporated herein byreference in its entirety).

There is a high mortality rate for patients who initially achieve returnof spontaneous circulation, which mortality rate is attributed to apathophysiological response involving the immune system and multipleorgans (Nolan et al., Resuscitation 79:350-379, 2008). Indeed, PRS ischaracterized by a large inflammatory response that has been linked toincreased oxidative stress which can lead to nerve cell malfunction ordeath and subsequently poor outcomes for patients.

For example, the release of oxygen free radicals, coagulation factors,complement-activation products, and cytokines may occur duringrevascularization after ischemia (reperfusion syndrome). Previousstudies have shown that non-survivors of cardiac arrest have asignificantly greater escalation of these pro-inflammatory biomarkers ascompared to survivors (Adrie et al., Circulation 106:562-568, 2002;Sipos et al., Resuscitation 81:603-608, 2010, which documents areincorporated by reference herein in their entireties). Moreover, therelease of these factors leads to marked activation of neutrophils withup-regulation of their surface adhesion molecules (Adrie et al., Curr.Opin. Crit. Care 10:208-212, 2004). The resulting leukocyte adhesion isan important step in vascular endothelium injury, leading to increasedmicrovascular permeability and thrombosis. Id. The elevation ofcirculating pro-inflammatory as well as immunomodulatory cytokines andadhesion molecules is a feature of PRS, which mimics the immunologicaldisorders observed in sepsis.

PRS treatment is time sensitive, and care of PRS patients mustaccommodate a range of patients, for example, patients who arehemodynamically stable as well as unstable and/or comatose patients. Thephases of PRS/post-cardiac arrest syndrome may be categorized as setforth in the following table:

TABLE 1 Phases of Post-Cardiac Arrest Syndrome* Phase DescriptionImmediate 0-20 min within the return of spontaneous circulation (ROSC)Early 20 min to 6-12 h Intermediate 6-12 h to 72 h Recovery 72 h todisposition Rehabilitation post-disposition *Source: Nolan et al.,Resuscitation 79: 350-379, 2008.

Others have noted that within the first 24 hours after the cardiacarrest or ischemic event, multifocal hypoxia leads to microcirculatorydysfunction, resulting in rapid release of toxic enzymes and freeradicals into the blood (Adrie et al., Circulation 106:562-568, 2002).Over the next 1 to 3 days, cardiac function and systemic functionimprove, but intestinal permeability also increases, which may lead tosepsis and/or multiple organ dysfunction. Id. Days after cardiac arrestserious infection may occur and/or the patient may decline rapidly anddie. Id.

Therapeutic hypothermia after ventricular fibrillation cardiac arrestimproves neurologic outcome and has been recommended forpost-resuscitation care. Therapeutic hypothermia was thought to benefitpatients because the cooling of the body would reduce the amount of thepro-inflammatory substances circulating in the cardiovascular system.However, a recent study in a pig model of cardiac arrest withhypothermia indicates that the inflammatory response still occurs (withcorresponding upregulation of markers of systemic inflammation) evenwhen the animals were cooled as early as possible during the arrest(Sipos et al., Resuscitation 81:603-608, 2010).

Sharp rises in various cytokines and soluble receptors occur in thebloodstream as early as 3 hours after cardiac arrest. Several cytokines,including IL-6, show greater elevation in nonsurvivors than in survivorsas well as in patients requiring vasopressor therapy compared with otherpatients (Adrie et al., Curr. Opin. Crit. Care 10:208-212, 2004).

However, cytokines and other blood components may be difficult to removefrom the blood, especially in a short period of time following loss ofcirculation/cardiac arrest. For example, cytokines and other toxins areoften bound to the blood protein albumin, and conventional dialysismembranes do not remove substantial quantities of these protein-boundtoxins from the blood. This is because protein-impermeable membranes aregenerally used in dialysis methods. Consequently, extracorporealcircuits such as continuous renal replacement therapies (CRRT), coupledplasma filtration adsorption (CPFA) and continuous veno-venoushemodiafiltration (CVVHDF) have been developed to minimizecell-associated cytokine concentrations in the blood of septic patients.However, most extracorporeal circuits to date function primarily asartificial kidneys or perfusion devices.

There remains a need for treatment methods that filter harmfulsubstances from the blood of a subject post-cardiac arrest and formethods of treating or preventing PRS in subjects having, or at risk ofhaving, PRS. There also remains a need for a device capable ofselectively removing blood components for the effective preventionand/or treatment of PRS.

SUMMARY OF THE INVENTION

Accordingly, there is provided a therapeutic device comprising tubing;at least one pump; and a column or filter configured to selectivelyremove leukocytes, cytokines, and/or other blood components from theblood of a patient having or at recognized risk of having PRS at a bloodflow rate through the filter or column of at least 2.5 L per hour toeffectively treat or prevent PRS. The therapeutic device may optionallycomprise a blood temperature regulator.

There is also provided such a device comprising a column or filter thatis capable of removing interleukins, tumor necrosis factor α (TNF-α),c-reactive protein (CRP), nuclear factor-kappa B (NF-κB) subunit p65,interferon-γ, elastase, inducible NO synthase, heme oxygenase-1, freeradicals, intracellular adhesion molecules, vascular cell adhesionmolecule-1, complement components, granulocyte-macrophagecolony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1(MCP-1), Regulated on Activation, Normal T Cell Expressed and Secreted(RANTES) protein, and/or von Willibrand factor (VWF). The interleukinsinclude, for example, IL-1β, IL-2, IL-4, IL-6, IL-10, and IL-15. Theintracellular adhesion molecules include ICAM1, ICAM2, ICAM3, ICAM4, andICAM5. The free radicals are not limited and may be, for example, freeiron radicals or free oxygen radicals. The complement componentsinclude, for example, C3a and terminal complement complex (TCC).

In an embodiment, the device may selectively remove IL-6.

In an embodiment, the device may be portable.

In an embodiment, the device may be configured for a blood filtrationrate of 2.5-5 L/hr.

There is also provided a device as described above, wherein the filteror column comprises a hydrogel layer to which one or more moleculescapable of selectively binding leukocytes, cytokines, and/or other bloodcomponents has been immobilized. In an embodiment, the hydrogelcomprises dextran.

The invention also provides a therapeutic device as described abovewhich comprises a surface treatment filter.

There is also provided a therapeutic device comprising tubing, at leastone pump, a blood temperature regulator, and a column or filter, whereinthe device is capable of detecting the presence and/or amount of solublePRS-inducing or -exacerbating blood components, and selectively removingor partially removing one or more of the detected blood components fromthe blood of a subject.

The invention also provides such a device further comprising one or moreof an air-free pressure chamber, a pressure sensor, an oxygenator, ablood leak detector, an air detector, a cooler, a heater, an LED touchscreen, and/or a battery.

In an embodiment, the LED touch screen displays information relating tothe nature and/or amount of one or more PRS-inducing or -exacerbatingblood components in the blood to be filtered. For example, the LED touchscreen may display information relating to IL-6 plasma concentrationlevels. The device may also be configured to detect and displayinformation about the nature and/or amount of the one or morePRS-inducing or -exacerbating blood components in the blood to befiltered within about 45 minutes or less after filtration has started.The device may also be configured to detect and display informationabout the nature and/or amount of the one or more PRS-inducing or-exacerbating blood components in the blood to be filtered in 30 minuteintervals and to adjust flow rate through the filter or column based onthe information.

In an embodiment, the device may be configured to increase flow ratethrough the filter or column when IL-6 plasma concentration levels aredetected above 200 μg/L after 45-75 minutes after filtering with thedevice.

There is also provided such a device in which the LED touch screendisplays information relating to the nature and/or amount of one or morePRS-inducing or -exacerbating blood components in the bloodpost-filtration.

There is also provided a device as described above, which adjusts flowrate through the filter or column to maintain IL-6 plasma concentrationlevels below 200 μg/L in post-filtration blood.

In an embodiment, the therapeutic device of the present invention may beconfigured to induce therapeutic hypothermia in the subject.

The device of the present invention may also be configured for automatedplasma recovery and pressure-driven automatic flow control.

In an embodiment, the filter or column may be present as part of adetachable filtration module. The detachable module may be exchanged orselected for insertion in the device depending upon the blood componentor blood components to be removed.

In another aspect, there is also provided a therapeutic device forfiltering blood comprising a pump, and a filtering module comprising oneor more cylinders and filter material on at least a partial innersurface of the one or more cylinders, the therapeutic device beingconfigured to send blood into and/or through the one or more cylindersalong a spiral path such that blood components that induce or exacerbatePRS in a subject, or a portion thereof, are selectively retained in theone or more cylinders. Such a device, may for example, slowly injectblood in an upward direction combined with a fast rotary motion to exerta centrifugal force on the blood sent into and/or through the one ormore cylinders, such that one or more of the blood components thatinduce or exacerbate PRS in a subject contact the filter material. In anembodiment, the therapeutic device may be configured to obtain acentrifugal force within the one or more cylinders of 10,000 to 100,000G.

In another system, biocompound-specific adhesion is used to filter theblood, rather than a size-based pore filtration. In one embodiment, aspiral-wound filter is constructed to provide a compact filter with alarge surface area over which the blood is flowed. The filter is made upof an outer housing in which the blood is contained, composed of acylinder side wall and two end caps (FIG. 5A). Inside the housing is thefilter element (FIG. 5B), whose filter inlet port and exhaust portprotrude through the walls of the end caps via sealed holes. The bloodflows in a spiral fashion from the fluid inlet port into the inner tubethen into the spiral space via the inlet exhaust ports. The blood flowsin a spiral fashion within the spiral space and because of the spiralshape, the blood is exposed to a very large surface area. So, forinstance, for a filter diameter of 6 inches and a length of 6 inches anda spacing between the layers in the spiral of 0.2 inches, the surfacearea of blood/filter contact is 900 square inches. The filter element isa laminate structure of a substantially impermeable, flexible butsemi-rigid substrate support layer, of a relatively blood-inertcomposition such as polyethylene or cellulose. Laminated to that surfaceis the active surface matrix, in some cases made of carboxymethyldextran to which molecules can be covalently attached using well-definedchemistries (see Lofas S, Johnsson B, J. Chem. Soc. Chem. Commun.21:1526-1528, 1990). The dextran layer creates a suspended hydrogel thatis conducive to adhering blood agents. In general, the carboxymethyldextran minimizes nonspecific binding of biomolecules to the surface andincreases the binding capacity of the surface. The surface chemistry ofthe dextran may be modified to provide a surface with altered propertiessuch as hydrophobic, lipophylic, or lower charge.

A pliant over-molded sealing and spacing ridge is over-molded onto theperimeter of the laminate structure such that when it is wound aroundthe inner tube, it provides multiple sealing functions: 1) it sealsagainst the inner tube; 2) it seals against the adjoining layers at thetwo ends so that blood fluid is forced to flow only spirally; 3) itseals against the outer tube; and when the filter element is placed intothe cylinder side wall and the two end caps are placed and compressedinto position before being glued or ultrasonically welded to thecylinder side wall, they seal against the end caps and side wall.

As described, for instance, in Yang et al., Lab Chip 5:1017-1023, 2005,the surface is functionalized to adhere to PRS-inducing or -exacerbatingblood components. For instance, for IL-8 specific adhesion, “twomonoclonal antibodies recognizing different epitopes of IL-8” may beused. “MAB208 is a mouse immunoglobulin G₁ (IgG₁) that was raisedagainst human IL-8 and then protein G column purified from mouse ascitesfluid by R & D Systems (Clone No. 6217.111; Cat. No. MAB208). JK8-2 is amouse IgG1 that was raised against human IL-8 and produced by Biolegend(San Diego, Calif.; Clone No. JK8-2; Cat. No. 508502). It was purifiedby protein G affinity chromatography and then biotinylated. As apolishing step, size-exclusion chromatography (Amersham FPLC with aSuperdex-200 gel filtration column) was applied by our laboratory toeliminate traces of other proteins such as albumin from both monoclonalantibodies. The antibody fractions were collected in HBS-EP buffer andconcentrated with Amicon Ultra Centrifugal Filter Devices (10 kDa) fromMillipore (Billerica, Mass.; Product No. UFC901024). The purity wasdetermined by SDS-PAGE and MALDI-TOF mass spectroscopy. Theconcentrations were measured using a Micro BCA Protein Assay Kit fromPierce (Rockford, Ill.; Cat. No. 23235).” Id. Other monoclonalantibodies may be used to bind to one or more of these PRS-inducing or-exacerbating blood components.

Alternatively, the surface matrix may be functionalized to adhere tofree iron in the bloodstream. Free iron, typically in the form of Fe³⁺,can be captured by iron-binding compounds such as siderophores that maybe used to functionalize the surface of the surface matrix. Siderophoresare iron-complexing compounds of low molecular weight that aresynthesized by bacteria and fungi, and serve to deliver the iron to themicrobes. Ferriooxamine is one example. Siderophores are classified intofive principal groups according to their chemical structures:hydroxamates, catecholates, carboxylates, heterocyclic compounds, andmixed types. All the natural siderophores are designed to chelate(adhere to) Fe(III) selectively (Reference: Inorganic Biochemistry ofIron Metabolism, Robert Crichton, 2001, Wiley and Sons).

The blood is circulated in the spiral fashion in the spiral space of thefilter element, flowing outwardly until it reaches the exit intake portsof the outer tube, through which the blood exits into the outer tube andfinally out the exhaust port. The device may employ pressure at theinlet port as well as negative pressures at the exhaust port. The filtermay be alternatively configured to have the blood flow spirally inwardtoward the central tube, in which case the center tube becomes theexhaust port and the outer tube becomes the intake port. The surfacematrix may be composed of alternative materials such as spunpolyethylene teraphthalate (PET), cellulose acetate, polyurethanes,nylon, polyacrylonitrile or polypropylene.

The semi-rigid substrate may be formed into the cylindrical spiral shapeby creating features on the inner tube that the over-molded ridge towhich the in-most edge of the semi-rigid substrate is affixed and thenwinding the semi-rigid substrate around the inner tube as a mandrel. Thesemi-rigid material may be a polymer that can be thermoformed and thematerial can be heated to soften it while the winding is occurring. Theinner mating surface of the end caps into which the filter element seatsmay be conically shaped so that when all the components are pressedtogether for the final assembly, the inner wall of the end caps pressinward on the over-molded sealing edge at the top and bottom of thefilter element, thus sealing the end-surfaces of the filter element. Inorder to improve sealing, the ends of the filter element may also besealed with a non-bioactive sealing agent like silicone.

The flexible semi-rigid support layer should have both a smooth surfaceand preferably a surface that may be treated with a material of lowbinding force to the blood so that it is conducive for maximal laminarflow along the surface of the semi-rigid support layer. On the otherhand, the surface matrix will be roughened which will result inturbulent, non-laminar flow along its surface. These two surfaceproperties will result in the blood having different velocities relativeto the inner and outer regions of the blood volume. This differentialvelocity will cause a rolling-mixing action of the blood volume, therebycausing enhanced contact of all the blood volume with the activatedsurface matrix, and further enhancing the removal of the agents.

There is also provided a filter or column comprising a filter materialcapable of removing leukocytes and/or soluble blood components from theblood of a subject having or at recognized risk of having PRS at a bloodflow rate through the filter of at least 2.5 L per hour to effectivelytreat or prevent PRS. The filter or column may selectively removecytokines from the blood.

There is also provided a system for determining a treatment procedurefor a subject having or at recognized risk of having PRS comprising amodule for obtaining a blood sample from the subject; a module formeasuring and/or identifying the presence, absence, or amount of one ormore biomarkers present in the blood of the subject after cardiacarrest, ischemia or other loss of circulation; a module and LED screencapable of determining and displaying a treatment procedure for thesubject based on the presence, absence, or amount of the measured and/oridentified one or more biomarkers; and an adjustable filter module.

The present invention also provides a method of treating or preventingPRS comprising filtering blood of a subject having or at recognized riskof having PRS with a device a described above.

There is also provided a method of treating or preventing PRS comprisingpassing the blood of a subject at risk of PRS through a deviceconfigured to remove leukocytes, cytokines, free radicals, vonWillibrand factor, and/or other blood components at a flow rate of atleast 2.5 L per hour to effectively treat or prevent PRS. In anembodiment, there is also provided such a method wherein ananticoagulant, a chelating agent, and/or a glucocorticoid is added tothe blood as it passes through the device. The anticoagulant may beAnticoagulant Citrate Dextrose Solution A (ACD-A) or heparin. There isalso provided such a method, wherein the device is configured forextracorporeal blood circulation. For example, the method may comprisefiltering the blood extracorporeally to remove leukocytes. Theleukocytes to be removed may be lymphocytes, granulocytes and/ormonocytes. In an embodiment, the method comprises partial removal ofperipheral neutrophils.

There is also provided a method of treating or preventing PRS comprisinginducing hypothermia in a subject at risk of PRS, and passing blood of asubject at risk of PRS through a device as described above.

In an embodiment, there is also provided a cylindrical filter elementcomprising a surface activated fiber sheet and a substrate support thatform a layer, the layer wound in a spiral about an inner tube; and aspace adjacent to at least a partial surface of the fiber sheet, thefilter element being configured to accommodate blood flow in a spiralpath and to allow blood to come into contact with the fiber sheet suchthat blood components that induce or exacerbate PRS in a subject, or aportion thereof, are selectively retained in the filter element. In anembodiment, such a cylindrical filter element may comprise a flexiblesemi-rigid support layer having a smooth surface and a surface treatedwith a material of low binding force in the blood. In an embodiment,such a cylindrical filter element may comprise a roughened surfacematrix for turbulent, non-laminar flow along its surface.

In an embodiment, there is provided a therapeutic device comprising afilter element comprising a surface activated filtering agent thatattracts free iron, and which is configured to selectively remove thefree iron from the blood of a patient having or at recognized risk ofhaving PRS at a blood flow rate through the filter element of at least2.5 L per hour to effectively treat or prevent PRS.

In an embodiment, there is provided a filter element comprising a filtermaterial having an enhanced surface area for efficient and selectiveremoval of one or more PRS-inducing or -exacerbating blood componentsfrom the blood of a patient having or at recognized risk of having PRSat a blood flow rate through the filter element of at least 2.5 L perhour to effectively treat or prevent PRS. In an embodiment, the filterelement may comprise carbon nanofibers or sintered nanoparticles. In anembodiment, the surface area of the filter material may be enhanced bychemical vapor deposition.

In another embodiment, there is provided a method of making a filterelement with an enhanced surface area, the method comprising obtaining afilter material capable of removing leukocytes and/or soluble bloodcomponents from the blood of a subject having or at recognized risk ofhaving PRS at a blood flow rate through the filter element of at least2.5 L per hour to effectively treat or prevent PRS, and couplingnanofibers to the filter material or sintering nanoparticles to thefilter material.

In another embodiment, there is provided a method of making a filterelement with an enhanced surface area, the method comprising obtaining afilter material capable of removing leukocytes and/or soluble bloodcomponents from the blood of a subject having or at recognized risk ofhaving PRS at a blood flow rate through the filter element of at least2.5 L per hour to effectively treat or prevent PRS, and exposing thefilter material to chemical vapor deposition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a portable device capable of removing leukocytes,cytokines, and/or other blood components from the blood of a patient toeffectively treat post-resuscitation syndrome.

FIG. 2 shows a cylindrical column for filtering blood of a subject thathas or is at risk of having post-resuscitation syndrome.

FIG. 3A shows a filter module for filtering blood of a subject that hasor is at risk of having post-resuscitation syndrome.

FIG. 3B shows three possible membranes that may be included in thefilter module for removing one or more types of cells and/or other bloodcomponents.

FIG. 4A provides a partial view of a conical-shaped cylinder having aninner surface comprising a membrane filter or surface treatment filter.

FIG. 4B shows a detachable filter module comprising multipleconical-shaped filters, housing for the filters, and a base.

FIG. 5A shows the outer housing for a filter element.

FIG. 5B shows a filter element, which may be placed in an outer housing.

FIG. 6 shows extracorporeal filtration of IL-6 from a subject.

FIG. 7 shows a flow diagram for one possible course of treatment orprevention for post-resuscitation syndrome with a device capable ofachieving a blood flow rate of at least 2.5 L/h.

FIG. 8 shows a flow diagram for one possible method for determining atreatment course for post-resuscitation syndrome.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly dictates otherwise. Forexample, reference to “a cytokine” would also mean that mixtures of oneor more cytokines can be present unless specifically excluded.

Except where otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot to be considered as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should be construed in light of the number of significantdigits and ordinary rounding conventions.

Additionally, the recitation of numerical ranges within thisspecification is considered to be a disclosure of all numerical valuesand ranges within that range. For example, if a range is from about 1 toabout 50, it is deemed to include, for example, 1, 7, 34, 46.1, 23.7, orany other value or range within the range.

The various embodiments disclosed herein can be used separately and invarious combinations unless specifically stated to the contrary.

Device

A device as invented by the inventors may comprise tubing, at least onepump, and a column or filter capable of selectively removing leukocytes,cytokines, and/or other blood components from the blood of a patienthaving or at recognized risk of having post-resuscitation syndrome (PRS)to effectively treat or prevent post-resuscitation syndrome. The devicemay be therapeutic and may function as a device to treat or preventpost-resuscitation syndrome and/or one or more symptoms ofpost-resuscitation syndrome. For example, the device may be capable ofinducing hypothermia in a subject, pump and receive blood from asubject, pump blood from a subject through one or more filter modules,filter blood of a subject to remove toxic substances that cause orexacerbate post-resuscitation syndrome, and/or return the blood of asubject to the subject. The device may function to pump bloodextracorporeally, for filtration, heating or cooling, or othertreatment.

In another embodiment, there is provided a therapeutic device comprisingtubing, at least one pump, a blood temperature regulator, and a columnor filter, wherein the device is capable of detecting the presenceand/or amount of soluble PRS-inducing or -exacerbating blood components,and selectively removing or partially removing one or more of thedetected blood components from the blood of a subject.

In an embodiment, there is provided a therapeutic device comprising apump, and a filtering module comprising one or more cylinders and filtermaterial on at least a partial inner surface of the one or morecylinders, the therapeutic device being configured to send blood intoand/or through the one or more cylinders along a spiral path such thatblood components that induce or exacerbate PRS in a subject, or aportion thereof, are selectively retained in the one or more cylinders.In such a device, and without being bound to a particular mechanism ofoperation, centrifugal force is exerted on the blood sent into and/orthrough the one or more cylinders, such that one or more of the bloodcomponents that induce or exacerbate PRS in a subject contact the filtermaterial. The device may, for example, slowly inject blood in an upwarddirection and simultaneously rotate the fluid contents to exert acentrifugal force on the blood sent into and/or through the one or morecylinders. In this way, the blood contacts the filter material on theinner surface of one or more cylinders and substances that induce orexacerbate PRS are selectively retained while the filtration productreturns to the base of the filtration module via gravity, where it maybe further circulated back to the subject. Such a device provides rapidand efficient removal and/or retention of selective bloodcomponents—even at high blood flow rates through the device. Thecentrifugal force within one or more cylinders of the device may be10,000 to 100,000 G; 20,000-80,000 G, 25,000-75,000 G, or 50,000 G.

In another embodiment, there is provided a device comprising tubing, atleast one pump, a blood temperature regulator, and a detachable modulecapable of removing leukocytes, cytokines, and/or other blood componentsfrom the blood of a patient to effectively treat or preventpost-resuscitation syndrome. There is also provided such a device,wherein the detachable module selectively removes cytokines up-regulatedduring post-resuscitation syndrome. There is also provided such a devicewherein the detachable module selectively removes free iron radicals.There is also provided such a device wherein the detachable module maybe exchanged or selected for insertion in the device depending upon theblood component to be removed. A cassette tubing system and slide statorpumps may be included and preparation time of the tubing may thereby bereduced. Arterial and venous tubing may be loaded simultaneously, andthe use of cassette tubing allows for correct position of air detectors.The slide stator pumps also provide for tubing set up without winding.

A device as provided herein may be capable of therapeutic apheresisand/or continuous renal replacement therapy. The device may, forexample, be capable of automated plasma recovery and/or may havepressure driven automatic flow control. The device may be capable ofautomatic priming and thereby reduced priming time compared toconventional devices. Reduced priming volumes and increased safety mayalso be achieved by automatic priming.

In an embodiment, the device may be high-volume hemofiltration device.The device may achieve blood flow rates of, for example, 1-400 mL/min.In a preferred embodiment, the device may be capable of blood flow ratesof 200-400, 300-375, or 350 mL/min.

In an embodiment, the device is configured to increase flow rate throughthe filter or column when IL-6 plasma concentration levels, or when thelevels of a different cytokine or blood component, are detected above200 μg/L. The plasma concentration levels are not particularly limited.For example, if IL-6 plasma concentration levels in a subject are above150-500 μg/L, the device may detect such concentration and adjust theflow rate through the filter or column accordingly. The device may alsoadjust flow rate through the filter or column to maintain plasmaconcentration levels of a PRS-inducing or -exacerbating blood componentbelow a certain toxic threshold. For example, the device may beconfigured to adjust flow rate through the filter or column to maintainIL-6 plasma concentration levels below 150, 175, 190, 200, 210, or 250μg/L in post-filtration blood.

Similarly, the timing of such detection and/or filtration/flow rateadjustment is not limited. The device may obtain measurements of bloodcomponent levels at any time, including, for example, 45 min, 50 min, 60min, 65 min, 70 min, or 75 min after collecting a sample from thesubject at risk of having or having post-resuscitation syndrome. Thedevice may be further configured to detect levels of blood componentssuch as cytokines, free radicals, etc., at intervals of 10 min, 15 min,20 min, 30 min., 45 min, and so on.

The device of the present invention will be capable of a range of bloodfiltration rates as well. For example, the blood filtration rate of thedevice as described herein may achieve a blood filtration rate of 0.9 to10 L/h, 1 to 9 L/h, 2 to 8 L/h, 2.5 to 5 L/h, 3, 4, 6, or 7 L/h.

In a preferred embodiment, the device may be configured forextracorporeal circulation. The device may be stationary or portable.The portable device may, for example, have wheels, and/or be of lightweight and compact, such that it may be conveniently carried,transported, or rolled to a patient at risk of post-resuscitationsyndrome.

Filters and Columns

The filter of the device is not particularly limited, and may be, forexample, selected from commercially available filters, etc. The filtermay be, for example, a leukocyte removing filter as described in U.S.Pat. Nos. 8,496,833; 7,641,794; and 7,655,146, each of which isincorporated by reference herein in its entirety. In an embodiment, thefilter may be a surface treatment filter.

Similarly, the column of the device is not particularly limited, and maybe a leukocytapheresis column or a commercially available column capableof removing leukocytes.

One of ordinary skill in the art will appreciate that the filter orcolumn may be selected based on the nature and/or amount of bloodcomponents to be removed and/or reduced. Filters and columns of theinvention may remove leukocytes, cytokines, and/or other bloodcomponents from the blood of a patient to effectively treat or preventpost-resuscitation syndrome. Leukocytes to be removed include, forexample, granulocytes (e.g., neutrophils, eosinophils, or basophils),macrophages, monocytes, and/or lymphocytes (e.g., B cells and T cells).Filters and columns of the invention may remove all cells of a certaintype or a partial amount. For example, the filters and/or columns of theinvention may partially remove peripheral neutrophils from the blood ofsubject having or at risk of having PRS. Similarly, filters and columnsof the invention may remove all cytokines of a certain type or just apartial amount or a percentage of one or more types of cytokine.Cytokines to be removed include any of the cytokines described herein.For example, the filter or column may be configured to reduce solubleIL-6 levels in the blood of a subject by 90%, 75%, 60%, 50%, 40%, etc.

The column or filter may also be configured to selectively remove freeiron, free iron radicals, complement components, von Willebrand factor,free oxygen radicals, etc.

The column or filter may have a volume of 25-500 mL, 50-300 mL, 100-200mL, 125-175 mL or 150 mL, and may be in the shape or a cylinder or cone.The column or filter may be 50-600 mm in height, 75-500 mm in height,100-400 mm in height, 125-350 mm in height, 150-300 mm in height,175-250 mm in height, 200-225 mm in height, 550, 450, or 375 mm inheight. In an embodiment, the device may comprise multipleconical-shaped filters or membranes which selectively retain or excludeblood components based on size, binding capacity of the filter ormembrane, or specificity with regard to, for example, cell type, proteincharge, or amino acid sequence.

The column may be 10-220 mm, 20-200 mm, 30-180 mm, 40-160 mm, 50-150 mm,75-100 mm, 60, 70, 80, 90, 110, 120, 130, 140, 170, or 190 mm indiameter.

The column or filter may comprise nonwoven fabric, such as nonwovenfabric comprising polyethylene terephthalate. In addition topolyethylene, other materials which may used as part of the column orfilter include hydrogels, dextran (e.g., carboxymethyl dextran),cellulose, gold, or glass. The materials may be used alone or incombination. For example, the column or filter may comprise materialcapable of removing leukocytes and/or soluble blood components from theblood of a subject having or at recognized risk of having PRS at a bloodflow rate through the filter of at least 2.5 L per hour to effectivelytreat or prevent PRS. The material may be such that is capable of, forexample, selectively and simultaneously removing 1, 2, 3 or more bloodcomponents from the blood of a subject having or at recognized risk ofhaving PRS at a blood flow rate through the filter of at least 1.0 L,1.5 L, 2.0 L, 2.5 L, 3.0 L, 3.5 L, 4.0 L, 4.5 L, 5.0 L, 10 L or more perhour.

The column or filter may comprise an enhanced surface area or anenhanced area to dimension ratio. For example, a surface activatedfiltering agent present in the filter or column may enhance the chemicalattraction of the filter or column material to one or more compounds.The surface area of the column or filter may be enhanced by nanofiberssuch as carbon nanofibers that are coupled to the surface. The highsurface area, low density, and high pore volume of such nanofibersincrease the functional filtration surface area of the column or filter.The surface area of the filter may also be enhanced by chemical vapordeposition (CVD). For example, a filter material such as carbonnanofibers may be exposed to chemical vapor deposition to yieldnanofiber-supported nanoparticles. Alternatively, the surface area maybe enhanced by nanoparticles sintered thereto by any process known tothose of skill in the art. The blood components may be efficiently andselectively removed from the blood during filtering via such a column orfilter having an enhanced surface area.

The column or filter may selectively remove inflammatory biomarkers fromthe blood. For example, the column or filter may be specifically adaptedto selectively remove cytokines from whole blood, either by directremoval of IL-6 or by removal of cells that produce them. For example,the column or filter may be specifically adapted to selectively removeIL-6 from whole blood, either by direct removal of IL-6 or by removal ofwhite blood cells that produce IL-6.

The column or filter may also be configured as a module. The module maybe detachable. The column or filter may be present as part of adetachable filtration module or separately. In an embodiment, forexample, a column for TNF-α may be detachable such that it may beremoved from the device, and a filter or column for removing IL-6 may beinserted in its place. In this way, the detachable module may beexchanged or selected for insertion in the device depending upon theblood component or blood components to be removed.

In one aspect, the column or filter is capable of removing toxins andharmful substances associated with post-resuscitation syndrome,including, but not limited to: interleukins (e.g., IL-1β, IL-2, IL-4,IL-6, IL-10, and IL-15), tumor necrosis factor α (TNF-α), interferon(e.g., interferon-γ), c-reactive protein (CRP), nuclear factor-kappa B(NF-κB) subunit p65, elastase, inducible NO synthase (iNOS), hemeoxygenase-1 (HO-1), free radicals (e.g., free iron radicals or freeoxygen radicals), intracellular adhesion molecules (e.g., ICAM1, ICAM2,ICAM3, ICAM4, ICAM5), vascular cell adhesion molecule-1, complementcomponents (e.g., terminal complement complex (TCC) or complementcomponents C3a (C3a)), granulocyte-macrophage colony-stimulating factor(GM-CSF), monocyte chemoattractant protein-1 (MCP-1), Regulated onActivation, Normal T Cell Expressed and Secreted (RANTES) protein, andvon Willibrand factor (VWF). The column or filter may also be configuredto remove white blood cells (e.g., lymphocytes, macrophages, monocytes,granulocytes), or substances secreted by any such white blood cells, redblood cells, or platelets. In one embodiment, the filter module orcolumn be configured to specifically remove one substance or moleculefrom the blood of a subject or configured to remove a combination of theabove substances. In another embodiment, removal) of white blood cellsmay be performed to prevent an increase in the level of productsproduced or secreted by white blood cells.

The column, filter, and/or device of the instant invention may besterilized by any number of methods, e.g., by gamma-ray sterilization,or by contacting the column, filter, and/or device with a sterilizationagent, such as alcohol.

Other Device Components

The device may comprise one or more pumps. The pump may be anycommercially available pump, for example, non-occlusive centrifugalpumps, slide stator pumps, etc. The pump may withdraw blood from thepatient and transport it through the device. The invention provides, forexample, a device comprising a pump that transports blood through anextracorporeal circuit or sub-circuit, or an infusion pump that deliversanticoagulants, liquid, solutes, substitute blood components, or othersubstances and compounds to blood. The one or more pumps of the deviceare not particularly limited. For example, the pump may be a belt-drivenpump. The device may also include a syringe pump, stator pump, or othertypes of pumps suitable for methods as described herein. The pump mayalso be any pump that provides excellent stability from low to highspeeds.

The tubing may be, for example, arterial and/or venous tubing. Thetubing may be made of any suitable material including plastic or rubber.

The device may comprise a blood temperature regulator for activating aheater or cooler. The heater may be a resistance heater such as a wirecoil. The heater may be in the form of a heat-generating surface. Thecooler may be in the form of a heat-absorbing surface. The heatabsorbing surface will generally comprise a metal foil wrapped around acatheter, typically having an exposed area of at least about 2 cm². Inan embodiment, the cooler may be a thermoelectric cooler. The componentsof the device, including the blood temperature regulator, cooler, etc.,may be configured to induce therapeutic hypothermia in a subject.

The device may comprise additional components or modules, such as anoxygenator, catheter, blood infuser, temperature sensor, etc. Theoxygenator provides oxygenated blood to be returned to the patient'sarterial system. The blood infuser may deliver large volumes of plasmasubstitute, blood substitute, or whole blood, optionally withpreservation and or resuscitation cocktails.

In aspects and/or embodiments, the device may comprise one or more of anair-free pressure chamber, a pressure sensor, a blood leak detector, anair detector, a scale, an LED touch screen, and/or a battery. Amongother functions the air-free pressure chamber may minimize contactbetween air and blood.

One or more of the components of the device may be heparin bonded.

A touch screen may display information relating to the nature and/oramount of one or more PRS-inducing or -exacerbating blood components inthe blood to be filtered. The touch screen may display informationrelated to, for example, IL-6 plasma concentration levels. The device ofthe present invention may also be configured to detect and displayinformation about the nature and/or amount of the one or morePRS-inducing or -exacerbating blood components in the blood to befiltered within about 45 minutes, 30 minutes, 25 minutes, 20 minutes, 10minutes, or less after filtration had started. A device as providedherein may be, for example, configured to detect and display informationabout the nature and/or amount of the one or more PRS-inducing or-exacerbating blood components in the blood to be filtered in 30 minute,25 minute, 20 minute, 15 minute, 5 minutes, or 1 minutes intervals. Adevice as described herein may also adjust flow rates through the filteror column based on the information that is detected and displayed.

System

There is also provided a system for determining a treatment procedurefor a subject having or at recognized risk of having PRS. The system maycomprise one or more of the following: a module for obtaining a bloodsample from the subject; a module for measuring and/or identifying thepresence, absence, or amount of one or more biomarkers present in theblood of the subject after cardiac arrest, ischemia or other loss ofcirculation; a module and LED screen capable of determining anddisplaying a treatment procedure for the subject based on the presence,absence, or amount of the measured and/or identified one or morebiomarkers; and an adjustable filter module. The system may be in theform of a kit or other assembly. The system may comprise devicecomponents as described herein, which components function in the contextof the system to assist in effectively treating or preventing PRS.

Methods of Treatment and/or Prevention of Post-Resuscitation Syndrome

The invention provides methods of treating or preventingpost-resuscitation syndrome comprising: passing the blood of a subjectat risk of post-resuscitation syndrome through a therapeutic deviceconfigured to remove leukocytes, cytokines, free radicals, vonWillibrand factor, and/or other blood components after cardiac arrest toeffectively treat or prevent post-resuscitation syndrome.

The present invention also provides a method of treating or preventingPRS comprising filtering blood of a subject having or at recognized riskof having PRS with a device a described above.

There is also provided a method of treating or preventingpost-resuscitation syndrome comprising inducing hypothermia in a subjectat risk of post-resuscitation syndrome, and passing blood of the subjectat risk of post-resuscitation syndrome through a device comprisingtubing, at least one pump, a blood temperature regulator, and a columnor filter, the device being capable of detecting the presence and/oramount of soluble PRS-inducing or -exacerbating blood components, andselectively removing or partially removing one or more of the detectedblood components from the blood of a subject.

There is also provided a method of treating or preventingpost-resuscitation syndrome comprising passing the blood of a subject atrisk of post-resuscitation syndrome through a device configured toremove leukocytes, cytokines, free radicals, von Willibrand factor,and/or other blood components at a flow rate of at least 2.5 L per hourto effectively treat or prevent post-resuscitation syndrome.

Methods as described above may also include addition of ananticoagulant, a chelating agent, and/or a glucocorticoid to the bloodas it passes through the device. The anticoagulant may be AnticoagulantCitrate Dextrose Solution A (ACD-A) or heparin.

Treatment methods may comprise filtering the blood of a subject havingor at recognized risk of having PRS with a device comprising tubing, atleast one pump, and a filter or column capable of selective removingleukocytes, cytokines, and/or other blood components from the blood of apatient having or at recognized risk of having PRS at a blood flow ratethrough the filter of at least 2.5 L per hour to effectively treat orprevent PRS. For example, the method may comprise filtering the bloodextracorporeally to remove, for example, leukocytes. The leukocytes tobe removed may be lymphocytes, granulocytes and/or monocytes. In anembodiment, the method comprises partial removal of leukocytes (e.g.,lymphocytes or peripheral neutrophils), or partial removal of one ormore cytokines (e.g., IL-4 or IL-6).

There is also provided a method of treating or preventingpost-resuscitation syndrome comprising inducing hypothermia in a subjectat risk of post-resuscitation syndrome, and passing blood of a subjectat risk of post-resuscitation syndrome through a device as describedabove which includes a blood temperature regulator.

In one aspect of the invention, there is provided a method of treatingchildren after extracorporeal circulation, e.g., for cardiac surgery.

In another aspect of the invention, there is provided a method ofhigh-volume hemofiltration. High volume hemofiltration may be used tofilter large quantities of blood rapidly. For example, high-volumehemofiltration may be used to achieve 100 L of fully balancedultrafiltration over an 8-hour period. High volume hemofiltration may beperformed, for example, at a rate of 180-220 ml/kg/h, 190-210 ml/kg/h,and preferably at 195-205 ml/kg/h. For example, high volumehemofiltration may be performed at 200 ml/kg/h for 8 hours. High volumehemofiltration may also be performed for 0.5-12 h, 1-10 h, 2-9 h, 3-8 h,4-6 h, or for 5 h. There is also provided similar methods of high-volumeultrafiltration.

High volume hemofiltration may be performed with or without inducinghypothermia in the subject. Induction of hypothermia may controlinflammatory processes and improve recovery and/or survival. Bodytemperature may be reduced to a desired temperature or range, e.g.,32-36° C., 33-35° C., or 34° C.

Timing of Treatment and/or Prevention

The timing and manner of treatment may vary depending upon severalfactors. Generally the sooner treatment begins after return ofspontaneous circulation, the better the therapeutic prospects for thesubject at risk of post-resuscitation syndrome. Treatment options and/orthe substance to be filtered may also depend upon the timing oftreatment. For example, treatment within 1 hour of cardiac arrest orcessation of circulatory function may comprise removal of white bloodcells which secret toxic enzymes into the blood stream. Treatment within24 h of cardiac arrest or cessation of circulatory function may compriseremoval of one or more toxic enzymes and/or free radicals, which resultfrom multifocal hypoxia and microcirculatory dysfunction that occurduring this period. Treatment and/or prevention may begin, however,prior to cardiac arrest, ischemia, or similar event. Methods oftreatment may also begin at 0 to 20 minutes, at 20 minutes to 6 hours,at 72 hours, etc., from return of spontaneous circulation (ROSC). Whentreatment methods include induction of hypothermia, body temperature isgenerally reduced soon after ischemia/surgery/loss of spontaneouscirculation, e.g., within 1 hour, 45 minutes, 30 minutes, 25 minutes, 15minutes or even 1 minute. When treatment methods include induction ofhypothermia, body temperature reduction may also be induced upon returnof spontaneous circulation, e.g., immediately after return ofspontaneous circulation, within 0-5 minutes, 6-20 minutes, 21-45minutes, or 46-60, or 90 minutes of return of spontaneous circulation.Hypothermia may be induced, for example, via infusion of cold saline,with ice bags, or by other conventional methods.

Duration and Manner of Administration

Treatments may be administered in a single session or in multiplesessions.

Subjects to be treated are not particularly limited. Subjects includepatients who have experienced cardiac arrest, post-cardiac arrest braininjury, post-cardiac arrest myocardial dysfunction, systemicischemia/reperfusion response, or persistent precipitating pathologysuch as cardiovascular disease, pulmonary disease, CNS disease,infection, hemorrhage, dehydration, etc. Subjects include any mammalhaving or at risk of having PRS, e.g., human subjects.

The blood circuit formed during the filtration process may bearterio-venous, whereby blood flows from an artery through a large borecannula into tubing, proceeds through a filter, and returns from thefilter to a vein. Alternatively, the blood circuit may be veno-venoussuch that blood flows from a vein to the filter and returns from thefilter to a vein. Ultrafiltrate may collect in a filter jacket, drainedthrough an ultrafiltrate line, discarded, and/or recycled either intothe blood circuit or elsewhere. Blood flow may return to the patient atthe wrist or radial artery or vein. Blood flow may also return to thepatient at a femoral artery or vein access point, e.g., at the innerthigh near the groin.

Optional Induction of Hypothermia

The invention provides methods of treating or preventingpost-resuscitation syndrome comprising optional induction of hypothermiain a subject. The induction of hypothermia may be therapeutic. Theinduction of hypothermia may, for example, be mild such that a patient'sbody temperature is reduced to, e.g., 33-36° C., moderate such that apatient's body temperature is reduced to, e.g., 28, 29, 30, 31, or 32°C., or deep such that a patient's body temperature is reduced to, e.g.,below 28° C.

The particulars shown herein are by way of example and for purposes ofillustrative discussion of embodiments of the present invention only andare presented in the cause of providing what is believed to be the mostuseful and readily understood description of the principles andconceptual aspects of the present invention. In this regard, no attemptis made to show structural details of the present invention in moredetail than is necessary for the fundamental understanding of thepresent invention, the description is taken with the drawings makingapparent to those skilled in the art how the forms of the presentinvention may be embodied in practice.

1-45. (canceled)
 46. A method for treating or preventing ischemia in asubject, comprising: removing blood from a subject, comprising movingthe blood from the subject through a first portion of a circuitcomprising a first portion of tubing; passing the removed blood from thefirst portion of the circuit through a filter at a blood flow rate of4-24 L per hour to selectively remove blood components comprising one ormore of: leukocytes, cytokines, interleukins, tumor necrosis factor α(TNF-α), c-reactive protein (CRP), nuclear factor-kappa B (NF-KB)subunit p65, interferon-γ, elastase, inducible NO synthase, hemeoxygenase-1, free radicals, intracellular adhesion molecules, vascularcell adhesion 55 molecule-I, complement components,granulocyte-macrophage colony-stimulating factor (GM-CSF), monocytechemoattractant protein-I (MCP-1), Regulated on Activation, Normal TCell Expressed and Secreted (RANTES) protein, and von Willibrand factor(VWF); and returning the filtered blood to the subject, comprisingpassing the filtered blood to the subject via a second portion of thecircuit comprising a second portion of tubing.
 47. The method of claim46, wherein the selectively removing the blood components comprisesremoving the interleukins comprising at least one of IL-1β, IL-2, IL-4,IL-6, IL-10, and IL-15.
 48. The method of claim 46, wherein theselectively removing the blood components comprises removing theintracellular adhesion molecules comprising at least one of ICAM1,ICAM2, ICAM3, ICAM4 and ICAM
 5. 49. The method of claim 46, wherein theselectively removing the blood components comprises removing freeradicals comprising at least one of free iron radicals and free oxygenradicals.
 50. The method of claim 46, wherein the selectively removingthe blood components comprises removing complement components comprisingat least one of C3a and terminal complement complex (TCC).
 51. Themethod of claim 46, wherein the removing of the blood from the subjectcomprises using a catheter inserted into the patient's body for use incarrying extracting the blood.
 52. The method of claim 46, comprisingoxygenating the blood prior to returning the filtered blood to thesubject.
 53. The method of claim 52, comprising oxygenating the bloodusing an oxygenator in supplying oxygen to be added to the blood. 54.The method of claim 52, wherein the method is used to treat ischemia.55. The method of claim 54, wherein the method is used to treat ischemiafollowing a heart attack.
 56. The method of claim 54, wherein the methodused to treat ischemia following a cardiac arrest.
 57. The method ofclaim 52, wherein the method is used to treat one or more ofpost-cardiac arrest brain injury, post-cardiac arrest myocardialdysfunction, reperfusion response, persistent pathology, cardiovasculardisease, pulmonary disease, CNS disease, infection, hemorrhage, anddehydration.
 58. The method of claim 52, wherein the selectivelyremoving the blood components comprises removing free radicals.
 59. Themethod of claim 52, wherein the selectively removing the bloodcomponents comprises removing oxygen free radicals.
 60. The method ofclaim 52, wherein the selectively removing the blood componentscomprises removing heme oxygenase-1.
 61. The method of claim 52, whereinpassing of the removed blood through the filter comprises passing theremoved blood through a therapeutic device comprising the filter, andwherein the circuit connects the device and the subject.
 62. The methodof claim 70, wherein passing of the removed blood through the filtercomprises passing the removed blood through the therapeutic device,wherein the therapeutic device displays information on a screen.
 63. Themethod of claim 71, wherein the therapeutic device comprises a whereinpassing of the removed blood through the filter comprises passing theremoved blood through the therapeutic device, wherein the therapeuticdevice displays information on a touch screen.
 64. The method of claim52, wherein the moving of the blood comprises using at least one pumpfor pumping the blood.
 65. The method of claim 52, comprising, prior tothe removing of the blood from the subject, inducing therapeutichypothermia of the subject.
 66. The method of claim 52, comprisinginducing therapeutic hypothermia of the subject by returning cooledblood to the subject.
 67. The method of claim 52, comprising using ablood temperature regulator in inducing therapeutic hypothermia of thesubject by returning cooled blood to the subject.
 68. The method ofclaim 52, comprising selectively removing the blood componentscomprising at least one of soluble or secreted blood components.
 69. Themethod of claim 68, comprising the passing of the removed blood throughthe filter, wherein the filter comprises a hydrogel layer to which oneor more molecules capable of binding one or more of the blood componentshas been immobilized.
 70. The method of claim 68, comprising the passingof the removed blood through the filter, wherein the filter comprises abase and one or more conical cylinders with a larger opening of the oneor more conical cylinders oriented away from the base.
 71. The method ofclaim 68, wherein a therapeutic device comprises the filter, and whereinthe therapeutic device exerts a centrifugal force on the blood withinthe one or more conical cylinders, thereby sending the blood into orthrough the one or more conical cylinders along a spiral path such thatthe soluble or the secreted blood components, or a portion thereof, areselectively retained in the one or more conical cylinders.
 72. Themethod of claim 46, wherein the passing of the removed blood from thefirst portion of the circuit through the filter at the blood flow rateof 4-24 L per hour comprises passing the removed blood from the firstportion of the circuit through the filter at a blood flow rate of 4-4.5L per hour.
 73. The method of claim 46, wherein the passing of theremoved blood from the first portion of the circuit through the filterat the blood flow rate of 4-24 L per hour comprises passing the removedblood from the first portion of the circuit through the filter at ablood flow rate of 4-5 L per hour.
 74. The method of claim 46, whereinthe passing of the removed blood from the first portion of the circuitthrough the filter at the blood flow rate of 4-24 L per hour comprisespassing the removed blood from the first portion of the circuit throughthe filter at a blood flow rate of 4-10 L per hour.
 75. The method ofclaim 46, wherein the method is used to treat or preventpost-resuscitation syndrome (PRS).
 76. The method of claim 46,comprising adjusting flow rate through the filter based on informationabout a nature or amount of one or more soluble or secreted bloodcomponents in the blood.
 77. The method of claim 46, comprisingadjusting flow rate through the filter based at least in part oninformation about a nature or amount of one or more soluble or secretedblood components to be filtered in 30 minute intervals.
 78. The methodof claim 46, comprising using pressure-driven automatic flow control inadjusting flow rate through the filter to maintain one or more solubleor secreted blood components in the blood below a toxicity threshold.79. The method of claim 46, comprising detecting IL-6 and adjusting flowrate through the filter to maintain IL-6 below a toxicity threshold.